EP1395590B1 - Dihydropyrrolo¬1,2-a|indole and tetrahydropyrido¬1,2-a|indole derivatives as prostaglandin d2 receptor antagonists - Google Patents

Dihydropyrrolo¬1,2-a|indole and tetrahydropyrido¬1,2-a|indole derivatives as prostaglandin d2 receptor antagonists Download PDF

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Publication number
EP1395590B1
EP1395590B1 EP02729708A EP02729708A EP1395590B1 EP 1395590 B1 EP1395590 B1 EP 1395590B1 EP 02729708 A EP02729708 A EP 02729708A EP 02729708 A EP02729708 A EP 02729708A EP 1395590 B1 EP1395590 B1 EP 1395590B1
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European Patent Office
Prior art keywords
alkyl
phe
halogen
optionally substituted
indol
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German (de)
English (en)
French (fr)
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EP1395590A2 (en
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Zhaoyin Wang
Christian Beaulieu
Claude Dufresne
Daniel Guay
Yves Leblanc
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Merck Canada Inc
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Merck Frosst Canada and Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds and methods for treating prostaglandin mediated diseases, and certain pharmaceutical compositions thereof. More particularly, the compounds of the invention are structurally different from steroids, antihistamines or adrenergic agonists, and are antagonists of the nasal and pulmonary congestion effects of D-type prostaglandins.
  • PGD2 is considered to be an important mediator in various allergic diseases such allergic rhinitis, atopic asthma, allergic conjunctivitis and atopic dermatitis. More recently, an article by Matsuoka et al. in Science (2000), 287:2013-7, describes PGD2 as being a key mediator in allergic asthma. In addition, patents such as US 4,808,608 refer to prostaglandin antagonists as useful in the treatment of allergic diseases, and explicitly allergic asthma. PGD2 antagonists are described in, for example, European Patent Application 837,052 and PCT Application WO98/25919, as well as WO99/62555.
  • the present invention provides novel compounds which are prostaglandin receptor antagonists; more particularly, they are prostaglandin D2 receptor (DP receptor) antagonists.
  • Compounds of the present invention are useful for the treatment of various prostaglandin-mediated diseases and disorders; accordingly the present invention provides a method for the treatment of prostaglandin-mediated diseases using the novel compounds described herein, as well as pharmaceutical compositions containing them.
  • the present invention relates to compounds of formula I: and pharmaceutically acceptable salts and hydrates thereof, wherein:
  • the invention also encompasses pharmaceutical compositions containing a compound of formula I, and methods for treatment or prevention of prostaglandin mediated diseases using compounds of formula I.
  • halogen or halo includes F, Cl, Br, and I.
  • alkyl refers to linear, branched and cyclic and bicyclic structures and combinations thereof, containing the indicated number of atoms.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sand t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl, 3,7-diethyl-2,2-dimethyl-4-propylnonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclopentylethyl, methyl substituted cyclopropyl, ethyl substituted cyclobutyl, adamant
  • Cycloalkylidene refers to the following bivalent radical where the points of attachement are on the same carbon atom:
  • Cycloalkylene refers to the following bivalent radical where the points of attachment are on different carbon atoms:
  • Phenylene refers to the following bivalent radical and includes 1,2-phenylene, 1,3-phenylene and 1,4-phenylene:
  • Haloalkyl means an alkyl group as described above wherein one or more hydrogen atoms have been replaced by halogen atoms, with up to complete substitution of all hydrogen atoms with halo groups.
  • C 1-6 haloalkyl for example, includes -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 and the like.
  • Alkoxy means alkoxy groups of a straight, branched or cyclic configuration having the indicated number of carbon atoms.
  • C 1-6 alkoxy for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.
  • Haloalkoxy means an alkoxy group as described above in which one or more hydrogen atoms have been replaced by halogen atoms, with up to complete substitution of all hydrogen atoms with halo groups.
  • C 1-6 haloalkoxy for example, includes -OCF 3 , -OCH 2 CF 3 , -OCF 2 CF 3 and the like.
  • Alkenyl means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-to-carbon double bond, wherein hydrogen may be replaced by an additional carbon-to-carbon double bond.
  • C 2-6 alkenyl, for example, includes ethenyl, propenyl, 1-methylethenyl, butenyl and the like.
  • Heterocyclyl refers to a non-aromatic ring having 1 to 4 heteroatoms said ring being isolated or fused to a second ring selected from 3- to 7-membered alicyclic ring containing 0 to 4 heteroatoms, aryl and heteroaryl, wherein said heteroatoms are independently selected from O, N and S.
  • Non-limiting examples of heterocyclyl include oxetanyl, 1,3-dithiacyclopentane, dihydrobenzofuran, and the like.
  • Aryl means a 6-14 membered carbocyclic aromatic ring system comprising 1-3 benzene rings. If two or more aromatic rings are present, then the rings are fused together, so that adjacent rings share a common bond. Examples include phenyl and naphthyl.
  • Het represents a 5-10 membered aromatic ring system containing one ring or two fused rings, 1-4 heteroatoms, selected from O, S and N. Het includes, but is not limited to, tetrazolyl, benzothienyl, quinolinyl, benzothiazolyl, furanyl, diazinyl, imidazolyl, isooxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyridyl, pyrrolyl, tetrazinyl, thiazolyl, thiadiazolyl, thienyl, triazinyl, triazolyl, 1H -pyrrole-2,5-dionyl, 2-pyrone, 4-pyrone, pyrrolopyridine, furopyridine and thienopyridine.
  • “Therapeutically effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treatment includes alleviating, ameliorating, relieving or otherwise reducing the signs and symptoms associated with a disease or disorder.
  • prophylaxis means preventing or delaying the onset or the progression of a disease or disorder, or the signs and symptoms associated with such disease or disorder.
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula I, and pharmaceutically acceptable excipients.
  • Y 1 is selected from a bond, O, S, NR a , CHR d , CHR d CHR d , C(O), C(O)CHR d , phenylene, and C 3-6 cycloalkylidene.
  • Y 1 is phenylene, S, C(O) or CH 2 ; in another subset Y 1 is S; in another subset Y 1 is C(O); in another subset Y 1 is CH 2 .
  • Ar is napthyl or phenyl each optionally substituted with one to three groups independently selected from R g .
  • Ar is 1-, or 2-napthyl.
  • Ar is phenyl optionally substituted with one to three groups independently selected from halogen, aryl, S(O) n C 1-6 alkyl optionally substituted with one to six halogen, C 1-6 alkyl optionally substituted with one to five halogen atoms, CN, CONR a R b , and C(O)R a , where R a and R b are as defined under formula I.
  • Ar is 4-chlorophenyl optionally substituted with a second halogen atom.
  • Ar in this embodiment include 1-naphthyl, 2-naphthyl, phenyl, 3-(n-butoxy)phenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2,4,6-trichlorophenyl, 2,4,5-trichlorophenyl, 2-, 3- or 4-biphenyl, 4-chloro-2-(methylsulfonyl)phenyl, 4-chloro-2-(carboxamido)phenyl, 2-cyano-4-chlorophenyl, 4-chloro-2-iodophenyl, 4-(trifluoromethyl)phenyl, 4-(methylsulfonyl)phenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophen
  • Ar is a heteroaryl selected from furyl, pyridyl, benzothiazolyl, quinolinyl and pyrimidinyl, each optionally substituted with one or two halogen atoms.
  • Y 2 is selected from CH 2 and CH 2 CH 2 .
  • Y 2 is CH 2 ; in another subset Y 2 is CH 2 CH 2 .
  • A is C 1-3 alkyl optionally substituted with one to four halogen atoms and Q is COOH or tetrazolyl.
  • A-Q is selected from CH 2 COOH, CF 2 COOH and CH(CH 3 )COOH.
  • A-Q is CH 2 COOH.
  • A includes CH 2 , CH 2 CH 2 , CH(CH 3 ), CH(CH 3 ) 2 , CHF, CHFCF 2 , CHCl, 1,1-cyclopropylidene, 1,2-cyclopropylene, and the like.
  • Q include COOH, CONH 2 , CONH(CH 3 ), SO 2 NH 2 , tetrazolyl, and the like.
  • R 1 , R 2 and R 3 are independently selected from hydrogen, CN, halogen, S(O) n C 1-3 alkyl, OC 1-6 alkyl (optionally substituted with one to six substituents selected from halogen, aryl, heteroaryl, OH and OC(O)R a ), C 1-6 alkyl (optionally substitued with one to eight groups selected from aryl, heteroaryl, halogen, NR a R b , C(O)R a , C(OR a )R a R b , SR a , and OR a , wherein aryl, heteroaryl and alkyl are each optionally substituted with one to six groups independently selected from halogen, CF 3 , and COOH), aryl, heteroaryl, heterocyclyl, C 2-6 alkenyl (optionally substituted with one to six groups independently selected from halogen and OR a ), C(O)OC
  • R 1 , R 2 and R 3 include hydrogen, fluorine, chlorine, bromine, iodine, methylsulfonyl, ethylsulfonyl, methylsulfinyl, methoxy, isopropyloxy, methylthio, benzyloxy, acetyl, trifluoroacetyl, 1-hydroxy-2,2,2-trifluoroethyl, 1-hydroxy-2-methylpropyl, 1-hydroxyethyl, 1-methoxyethyl, 1-methoxypropyl, 1-methoxy-2,2,2-trifluoroethyl, 1-hydroxypropyl, 1-methoxypropyl, 1-methylthioethyl, ethyl, n-propyl, isopropyl, 3-pentyl, ethenyl, 2-propenyl, 2-penten-3-yl, phenyl, 4-chlorophenyl, 2-methylphenyl, 3-(1-pyrazo
  • R 1 is hydrogen.
  • R 1 is hydrogen
  • A-Q is CH 2 COOH
  • R 2 is selected from halogen, S(O) n C 1-3 alkyl, OC 1-6 alkyl (optionally substituted with aryl), CN, C 2-6 alkenyl, 1- and 2-methyltetrazolyl, 1-methylpyrrolyl and C 1-6 alkyl.
  • R 1 is hydrogen
  • A-Q is CH 2 COOH
  • R 3 is selected from halogen, S(O) n C 1-3 alkyl, OC 1-6 alkyl, C(O)R a , C 1-6 alkyl (optionally substitued with 3 to 6 halogen atoms, and 0 or 1 group selected from OR a , SR a ,), C 2-6 alkenyl, C 5-8 cycloalkenyl, phenyl (optionally substituted with a group selected from C 1-3 alkyl, OR a and pyrazolyl), naphthyl, and heteroaryl selected from pyrrolyl, thienyl, pyrazolyl, quinolinyl, benzothienyl, isoxalyl, pyridyl, each of which is optionally substituted with C 1-3 alkyl.
  • R 4 and R 5 are each independently selected from H and C 1-4 alkyl optionally substituted with one to six halogen atoms, preferably fluorine; or R 4 is OR a wherein R a is as defined under formula I, preferably hydrogen; or R 4 and R 5 attached to the same carbon atom represent an oxo. In one subset R 4 and R 5 are each hydrogen.
  • formula I are compounds of formula Ib: wherein Ar and R 1 - R 5 are as defined under formula I and Y 1 is O, S, C(O) or CH 2 . In one subset, R 4 and R 5 are each hydrogen, and R 2 and R 3 represent one or two non-H substituent. In another subset of formula Ib are compounds of formula Ic: wherein Y 1 is C(O), CH 2 or S, R and R' are independently hydrogen, halogen, cyano, C 1-3 alkanoyl or CF 3 , and R 2 and R 3 are each a non-hydrogen substituent.
  • R 2 is selected from halogen, S(O) n C 1-3 alkyl, OC 1-6 alkyl (optionally substituted with aryl), CN, C 2-6 alkenyl, 1- or 2-methyltetrazolyl, 1-methylpyroolyl and C 1-6 alkyl.
  • R 3 is selected from halogen, S(O) n C 1-3 alkyl, OC 1-6 alkyl, C(O)R a , C 1-6 alkyl (optionally substitued with 3 to 6 halogen atoms, and 0 or 1 group selected from OR a , SR a ,), C 2-6 alkenyl, C 5-8 cycloalkenyl, phenyl (optionally substituted with a group selected from C 1-3 alkyl, OR a and pyrazolyl), naphthyl, and heteroaryl selected from pyrrolyl, thienyl, pyrazolyl, quinolinyl, benzothienyl, isoxalyl, pyridyl, each of which is optionally substituted with C 1-3 alkyl.
  • R 2 is F
  • R is Cl
  • R' is hydrogen or halogen.
  • R 3 is selected from halogen, S(O) n C 1-3 alkyl, OC 1-6 alkyl, C(O)R a , C 1-6 alkyl (optionally substitued with 3 to 6 halogen atoms, and 0 or 1 group selected from OR a , SR a ,), C 2-6 alkenyl, C 5-8 cycloakenyl, phenyl (optionally substituted with a group selected from C 1-3 alkyl, OR a and pyrazolyl), naphthyl, and heteroaryl selected from pyrrolyl, thienyl, pyrazolyl, quinolinyl, benzothienyl, isoxalyl, pyridyl, each of which is optionally substituted with C 1-3
  • tautomers Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers.
  • the individual tautomers, as well as mixtures thereof, are encompassed with compounds of formula I.
  • Compounds of the formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof.
  • a suitable solvent for example methanol or ethyl acetate or a mixture thereof.
  • the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.
  • any enantiomer of a compound of the general formula I or Ia may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
  • salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • references to the compound of formula I are meant to also include the pharmaceutically acceptable salts.
  • prostaglandin receptors The ability of compounds of formula I to interact with prostaglandin receptors makes them useful for preventing or reversing undesirable symptoms caused by prostaglandins in a mammalian, especially human subject.
  • This mimicking or antagonism of the actions of prostaglandins indicates that the compounds and pharmaceutical compositions thereof are useful to treat, prevent, or ameliorate in mammals and especially in humans: respiratory conditions, allergic conditions, pain, inflammatory conditions, mucus secretion disorders, bone disorders, sleep disorders, fertility disorders, blood coagulation disorders, trouble of the vision as well as immune and autoimmune diseases.
  • such a compound may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer.
  • Compounds of formula I may also be of use in the treatment and/or prevention prostaglandin-mediated proliferation disorders such as may occur in diabetic retinopathy and tumor angiogenesis.
  • Compounds of formula I may also inhibit prostanoid-induced smooth muscle contraction by antagonizing contractile prostanoids or mimicking relaxing prostanoids and hence may be used in the treatment of dysmenorrhea, premature labor and eosinophil related disorders. More particularly compounds of formula I are antagonists of prostaglandin D2.
  • another aspect of the invention provides a method of treating or preventing a prostaglandin mediated disease comprising administering to a mammalian patient in need of such treatment a compound of formula I in an amount which is effective for treating or preventing said prostaglandin mediated disease.
  • Prostaglandin mediated diseases include, but are not limited to, allergic rhinitis, nasal congestion, rhinorrhea, perennial rhinitis, nasal inflammation, asthma including allergic asthma, chronic obstructive pulmonary diseases and other forms of lung inflammation; sleep disorders and sleep-wake cycle disorders; prostanoid-induced smooth muscle contraction associated with dysmenorrhea and premature labor; eosinophil related disorders; thrombosis; glaucoma and vision disorders; occlusive vascular diseases; congestive heart failure; diseases or conditions requiring a treatment of anti-coagulation such as post-injury or post surgery treatment; inflammation; gangrene; Raynaud's disease; mucus secretion disorders including cytoprotection; pain and migraine; diseases requiring control of bone formation and resorption such as for example osteoporosis; shock; thermal regulation including fever; and immune disorders or conditions in which immunoregulation is desirable. More particularly the disease is to be treated is one mediated by prostaglandin D2 such as nasal congestion,
  • a method of heating or preventing a prostaglandin mediated disease comprising administering to a mammalian patient in need of such treatment a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease, wherein the prostaglandin mediated disease is nasal congestion, rhinitis including allergic and perennial rhinitis, and asthma including allergic asthma.
  • in another embodiment of the present invention is a method of treating or preventing a prostaglandin D2-mediated disease comprising administering to a mammalian patient in need of such treatment a compound of formula I in an amount which is effective for treating or preventing a prostaglandin D2 mediated disease wherein said prostaglandin D2 mediated disease is nasal congestion or asthma.
  • in another embodiment of the present invention is a method for the treatment of nasal congestion in a patient in need of such treatment which comprises administering to said patient a therapeutically effective amount of a compound of formula I.
  • in yet another embodiment of the present invention is a method for the treatment of asthma, particularly allergic asthma, in a patient in need of such treatment which comprises administering to said patient a therapeutically effective amount of a compound of formula I.
  • in yet another embodiment of the present invention is a method for the treatment of allergic rhinitis, including seasonal allergic rhinitis and perennial allergic rhinitis, in a patient in need of such treatment which comprises administering to said patient a therapeutically effective amount of a compound of formula I.
  • prophylactic or therapeutic dose of a compound of formula I will, of course, vary with the nature and the severity of the condition to be treated and with the particular compound of formula I and its route of administration. It will also vary according to a variety of factors including the age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination and response of the individual patient. In general, the daily dose from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 10 mg per kg. On the other hand, it may be necessary to use dosages outside these limits in some cases.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 0.05 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 99.95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 0.1 mg to about 0.4 g of an active ingredient, typically 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, or 400 mg.
  • compositions comprising a compound of formula I with a pharmaceutically acceptable carrier.
  • composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula I, additional active ingredient(s), and pharmaceutically acceptable excipients.
  • compounds of formula I may be administered orally, by inhalation spray, topically, parenterally or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • the compound of the invention is effective in the treatment of humans.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water-miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water-miscible solvents such as propylene glycol, PEGs and ethanol
  • an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoole
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • colouring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavouring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffm or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.
  • compound of formula I may be co-administered with other therapeutic agents.
  • the present invention provides pharmaceutical compositions for treating prostaglandin mediated diseases comprising a therapeutically effective amount of a compound of formula I and one or more other therapeutic agents.
  • Suitable therapeutic agents for combination therapy with a compound of formula I include: (1) a prostaglandin D2 antagonist such as S-5751; (2) a corticosteroid such as triamcinolone acetonide; (3) a ⁇ -agonist such as salmeterol, formoterol, terbutaline, metaproterenol, albuterol and the like; (4) a leukotriene modifier, including a leukotriene antagonist or a lipooxygenase inhibitor such as montelukast, zafirlukast, pranlulkast, or zileuton; (5) an antihistamine such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyprohepta
  • Ariflo, roflumilast (13) antagonists of the chemokine receptors, especially CCR-1, CCR-2, and CCR-3; (14) cholesterol lowering agents such as HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, and other statins), sequestrants (cholestyramine and colestipol), nicotinic acid, fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), and probucol; (15) anti-diabetic agents such as insulin, sulfonylureas, biguanides (metformin), ⁇ -glucosidase inhibitors (acarbose) and glitazones (troglitazone, pioglitazone, englitazone, rosiglitazone and the like); (16)
  • the invention encompasses a method of treating prostaglandin D2 mediated diseases comprising: administration to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of formula I, optionally co-administered with one or more of such ingredients as listed immediately above.
  • Indole 1 can be alkylated with a halide at the 3-position to give 2 under basic conditions.
  • Compound 2 can be halogenated at the 2-position to provide 3, which is alkylated with an approprate halide to yield 4.
  • the acetal group in 4 can be hydrolyzed to give aldehyde 5.
  • Wittig reaction of 5 with a phosphorane provides unsaturated ester 6.
  • compound 6 cyclises to give 7. Hydrogenation of 7, followed by basic hydrolysis yields the final product 9.
  • Indole 1 can be sulphenylated with a disulfide at the 3-position to give 10 under basic conditions.
  • Compound 10 can be transformed to the final product 17 following the same sequences as described in Method 1.
  • the intermediate aldehyde 13 can be prepared by the methods described in Scheme 3.
  • Intermediate indole 25 may be prepared by the method presented in Scheme 4.
  • Benzaldehyde 18 is condensed with N 3 CH 2 CO 2 Me under basic conditions to provide ester 19, which may be converted to indole 20 by thermolysis.
  • Sulphenylation of indole 20 with ClSAr gives 21, which is then alkylated with an appropriate bromo-ester to yield diester 22.
  • Base promoted cyclization of 22 affords keto-ester 23, which, upon decarboxylation, provides ketone 24.
  • Wittig reaction of 24, followed by hydrogenation and hydrolysis affords the final product 27.
  • compound with six-membered ring can be prepared by the sequence described in Scheme 6. Reformatsky reaction on 30 provides alcohol 35a. Deoxygenation of 35a provides ester 32a, which is then sulphenylated with ClSAr to provide 26. Basic hydrolysis of 26 provides the target compound 27.
  • R 1 , R 2 or R 3 X (X could be: Cl, Br, I, OTf), then alkyl methanesulfonyl, cyano, aryl, heteroaryl and heterocycle could be introduced on the indole scaffold by metal-catalyzed cross-coupling reactions on 36a and/or 36c as described in Scheme 8.
  • metal halogen exchange on 36e and 36g could be done and the resulting organometallic species could be added to an electrophile such as alkyl disulfides and aldehydes as described in Scheme 9.
  • indole 41 may be prepared from aniline 39 and an ⁇ -substituted acetoacetate 40. Decarboxylation of 41 provides indole 42, which can then be converted to the target compound 43 by following the sequences described in Scheme 1-3.
  • 3-Substituted indole 2 can also be prepared by the method depicted in Scheme 12.
  • Indole 1 can be silylated with a trialkylsilyl halide under basic conditions to give silylated indole 44.
  • Bromination of 44 provides 45, which may be lithiated with alkyllithium and alkylated with an appropriate halide to afford 3-substituted indole 2.
  • the compounds substituted with a variety of alkoxy, aryloxy or heteroaryloxy at the 6-positions of the indole structure can be synthesized according to the reaction sequence depicted in Scheme 13.
  • Intermediate 47 can be prepared by the methods described in Method 3. Methylsulfonylation and demethylation of 47 provide phenol 48, which can react with a variety of alkyl halides, aryl halides or heteroaryl halides and a base to yield 49. Sulphenylation and hydrolysis under the reaction conditions described in Method 3 may afford the final compound 50.
  • the compounds substituted with a variety of alkyl, alkenyl or aryl at the 8-positions of the indole structure can be synthesized according to the reaction sequence depicted in Scheme 15.
  • 3-substituted methylene indole can be prepared by using the sequence described in Scheme 16. Indole 36i is alkylated under acidic condition to give 3-substituted indole 55 which is hydrolyzed under basic condition to afford 56.
  • 3-carbonyl indole can be prepared by using the sequence described in Scheme 17. Indole 36i is acylated under Friedel-Craft condition to give 3-carbonyl indole 57 which is hydrolyzed under basic condition to afford 58.
  • 3-alpha methyl indole can be prepared by using the sequence described in Scheme 18.
  • Acid 58 is esterified to the t-Butyl ester 59 which after Wittig olefination gives the vinyl indole 60.
  • the vinyl group of indole 60 is reduced by hydrogenation with Pd/C to give 61 which is hydrolyzed under acidic condition with TFA to afford 62.
  • Oxo pyrrolo indole can be prepared by using the sequence described in Scheme 19.
  • the indole 20 was reduced to the alcohol 63 with DIBAL.
  • Oxidation of 63 with Dess-Martin periodinane gives the aldehyde 64 which can be converted to unsaturated ester 65 after Wittig reaction with a phosphorane.
  • Addition of the anion of diethyl malonate to unsaturated ester 65 and decarboxylation of the resulting indole 66 gives 67.
  • the indole 67 is sulphenylated with ClSAr to give 68 which is hydrolyzed under acidic condition to give the target compound 69.
  • R 3 X (X could be: Cl, Br, I, OTf) alkyl group, methane sulfonyl, heteroaryl and heterocycle could be introduced on the indole scaffold by metal-catalyzed cross-coupling reactions on 68a to yield 69a as described in Scheme 20.
  • 6-Hydroxy indole derivative 48 can be converted into triflate 70, which is subjected to a transition metal catalyzed coupling reaction with i-Pr 3 SiSK to give 71. Desilylation of 71 followed by alkylation with R a X can provide 72. Sulphenylation reaction of 72 and aqueous hydrolysis yield the desired product 73 .
  • Compounds of formula I can be tested using the following assays to determine their prostanoid antagonist or agonist activity in vitro and in vivo and their selectivity.
  • the prostaglandin receptor activities demonstrated are DP, EP 1 , EP 2 , EP 3 , EP 4 , FP, IP and TP.
  • Prostanoid receptor cDNAs corresponding to full length coding sequences are subcloned into the appropriate sites of mammalian expression vectors and transfected into HEK 293(ebna) cells.
  • HEK 293(ebna) cells expressing the individual cDNAs are grown under selection and.individual colonies are isolated after 2-3 weeks of growth using the cloning ring method and subsequently expanded into clonal cell lines.
  • HEK 293(ebna) cells are maintained in culture, harvested and membranes are prepared by differential centrifugation, following lysis of the cells in the presence of protease inhibitors, for use in receptor binding assays.
  • Prostanoid receptor binding assays are performed in 10 mM MES/KOH (pH 6.0) (EPs, FP and TP) or 10 mM HEPES/KOH (pH 7.4) (DP and IP), containing 1 mM EDTA, 10 mM divalent cation and the appropriate radioligand.
  • the reaction is initiated by addition of membrane protein.
  • Ligands are added in dimethylsulfoxide which is kept constant at 1 % (v/v) in all incubations.
  • Non-specific binding is determined in the presence of 1 ⁇ M of the corresponding non-radioactive prostanoid. Incubations are conducted for 60 min at room temperature or 30 °C and terminated by rapid filtration. Specific binding is calculated by subtracting non specific binding from total binding. The residual specific binding at each ligand concentration is calculated and expressed as a function of ligand concentration in order to construct sigmoidal concentration-response curves for determination of ligand affinity.
  • Whole cell second messenger assays measuring stimulation (EP 2 , EP 4 , DP and IP in HEK 293(ebna) cells) or inhibition (EP 3 in human erythroleukemia (HEL) cells) of intracellular cAMP accumulation or mobilization of intracellular calcium (EP 1 , FP and TP in HEK 293(ebna) cells stably transfected with apo-aequorin) are performed to determine whether receptor ligands are agonists or antagonists.
  • cAMP assays cells are harvested and resuspended in HBSS containing 25 mM HEPES, pH 7.4.
  • Incubations contain 100 ⁇ M RO-20174 (phosphodiesterase type IV inhibitor, available from Biomol) and, in the case of the EP 3 inhibition assay only, 15 ⁇ M forskolin to stimulate cAMP production. Samples are incubated at 37°C for 10 min, the reaction is terminated and cAMP levels are then measured.
  • For calcium mobilization assays cells are charged with the co-factors reduced glutathione and coelenterazine, harvested and resuspended in Ham's F12 medium. Calcium mobilization is measured by monitoring luminescence provoked by calcium binding to the intracellular photoprotein aequorin. Ligands are added in dimethylsulfoxide which is kept constant at 1 % (v/v) in all incubations.
  • second messenger responses are expressed as a function of ligand concentration and both EC 50 values and the maximum response as compared to a prostanoid standard are calculated.
  • the ability of a ligand to inhibit an agonist response is determined by Schild analysis and both K B and slope values are calculated.
  • Animal preparation Healthy adult sheeps (18-50 kg) are used. These animals are selected on the basis of a natural positive skin reaction to an intradennal injection of Ascaris suum extract.
  • NAR Nasal airway resistance
  • a topical anaesthesia (2% lidocaine) is applied to the nasal passage for the insertion of a nasotracheal tube.
  • the maximal end of the tube is connected to a pneumotachograph and a flow and pressure signal is recorded on an oscilloscope linked to a computer for on-line calculation of NAR.
  • Nasal provocation is performed by the administration of an aerosolized solution (10 puffs/nostril). Changes in the NAR congestion are recorded prior to and for 60-120 minutes post-challenge.
  • Animal preparation Healthy adult male cynomologus monkeys (4-10 kg) are used. These animals are selected on the basis of a natural positive skin reaction to an intradermal injection of Ascaris suum extract. Before each experiment, the monkey selected for a study is fasted overnight with water provided at libitum. The next morning, the animal is sedated with ketamine (10-15 mg/kg i.m.) before being removed from its home cage. It is placed on a heated table (36°C) and injected with a bolus dose (5-13 mg/kg i.v.) of propofol.
  • the animal is intubated with a cuffed endotracheal tube (4-6 mm I.D.) and anaesthesia is maintained via a continuous intravenous infusion of propofol (25-30 mg/kg/h).
  • Vital signs heart rate, blood pressure, respiratory rate, body temperature are monitored throughout the experiment.
  • Measurements of nasal congestion A measurement of the animal respiratory resistance is taken via a pneumotachograph connected to the endotracheal tube to ensure that it is normal. An Ecovision accoustic rhinometer is used to evaluate nasal congestion. This technique gives a non-invasive 2D echogram of the inside of the nose. The nasal volume and the minimal cross-sectional area along the length of the nasal cavity are computed within 10 seconds by a laptop computer equipped with a custom software (Hood Laboratories, Mass, U.S.A.). Nasal challenge is delivered directly to the animal's nasal cavity (50 ⁇ L volume). The changes in nasal congestion are recorded prior to and for 60-120 minutes post-challenge. If nasal congestion occurs, it will translate into a reduction in the nasal volume.
  • the test procedure involves placing trained squirrel monkeys in chairs in aerosol exposure chambers.
  • pulmonary mechanics measurements of respiratory parameters are recorded for a period of about 30 minutes to establish each monkey's normal control values for that day.
  • compounds are dissolved or suspended in a 1% methocel solution (methylcellulose, 65HG, 400 cps) and given in a volume of 1 mL/kg body weight.
  • methocel solution methylcellulose, 65HG, 400 cps
  • a DeVilbiss ultrasonic nebulizer is utilized. Pretreatment periods vary from 5 minutes to 4 hours before the monkeys are challenged with aerosol doses of either PGD2 or Ascaris suum antigen; 1:25 dilution.
  • each minute of data is calculated by computer as a percent change from control values for each respiratory parameter including airway resistance (R L ) and dynamic compliance (C dyn ).
  • the results for each test compound are subsequently obtained for a minimum period of 60 minutes post-challenge which are then compared to previously obtained historical baseline control values for that monkey.
  • the overall values for 60 minutes post-challenge for each monkey are averaged separately and are used to calculate the overall percent inhibition of mediator or Ascaris antigen response by the test compound. For statistical analysis, paired t-test is used. (References: McFarlane, C.S. et al., Prostaglandins, 28, 173-182 (1984) and McFarlane, C.S. et al., Agents Actions, 22, 63-68 (1987).)
  • Animal Preparation Adult sheep with a mean weight of 35 kg (range, 18 to 50 kg) are used. All animals used meet two criteria: a) they have a natural cutaneous reaction to 1:1,000 or 1:10,000 dilutions of Ascaris suum extract (Greer Diagnostics, Lenois, NC); and b) they have previously responded to inhalation challenge with Ascaris suum with both an acute bronchoconstriction and a late bronchial obstruction (W.M. Abraham et al., Am. Rev. Resp. Dis., 128, 839-44 (1983)).
  • Transpulmonary pressure the difference between tracheal pressure and pleural pressure, is measured with a differential pressure transducer (DP45; Validyne Corp., Northridge, CA).
  • DP45 differential pressure transducer
  • R L pulmonary resistance
  • the signals of flow and transpulmonary pressure are recorded on an oscilloscope (Model DR-12; Electronics for Medicine, White Plains, NY) which is linked to a PDP-11 Digital computer (Digital Equipment Corp., Maynard, MA) for on-line calculation of R L from transpulmonary pressure, respiratory volume obtained by integration and flow. Analysis of 10-15 breaths is used for the determination of R L .
  • Step 1 3-[(4-Chlorophenyl)sulfanyl]-1 H -indole
  • Step 2 (+/-)-[9-[(4-Chlorophenyl)sulfanyl]-2,3-dihydro-1H-pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 Ethyl 6-(methylsulfanyl)-1 H -2-indolecarboxylate
  • Step 2 1 H -6-Indolyl methyl sulfide
  • Step 3 1 H -6-Indolyl methyl sulfone
  • Step 4 (+/-)-[10-[(4-chlorophenyl)sulfanyl]-3-(methylsulfonyl)-6,7,8,9-tetra-hydropyrido[1,2- a ]indol-9-yl]acetic acid
  • Step 3 Ethyl 5,7-dibromo-3-(4-chlorophenyl)-4-(methylsulfanyl)-1 H -indole-2-carboxylate
  • Step 4 Ethyl 3-(4-chlorophenyl)-4-(methylsulfanyl)-1 H -indole-2-carboxylate
  • step 3 To a solution of the indole of step 3 (2.1g) in 200 mL of EtOAc was added 5% palladium on carbon (1g). The mixture was shaken under H 2 atmosphere (50 psi) for 24 hours, filtered on a silica gel pad eluted with EtOAc and the filtrate concentrated to give the title compound as a white solid (1.5 g) used as such.
  • Step 5 3-(4-Chlorophenyl)-4-(methylsulfanyl)-1 H -indole-2-carboxylic acid
  • Step 6 3-(4-Chlorophenyl)-1 H -indol-4-yl methyl sulfide
  • Step 7 2-Bromo-3-(4-chlorophenyl)-1 H -indol-4-yl methyl sulfide
  • Step 8 Ethyl 4-[2-bromo-3-(4-chlorophenyl)-4-(methylsulfanyl)-1 H -indol-1-yl]butanoate
  • Step 9 4-[2-Bromo-3-(4-chlorophenyl)-4-(methylsulfanyl)-1 H -indol-1-yl]butanal
  • Step 10 Ethyl(2 E , Z )-6-[2-bromo-3-(4-chlorophenyl)-4-methylsulfanyl)-1 H- indol-1-yl]-2-hexenoate
  • Step 11 Ethyl(2- E , Z )-(10-(4-chlorophenyl)-1-(methylsulfanyl)-7,8-dihydropyrido[1,2- a ]indol-9(6 H )-ylidene)ethanoate
  • Step 12 (+/-)-Ethyl[10-(4-chlorophenyl)-1-(methylsulfanyl)-6,7,8,9-tetrahydropyrido[1,2- a ]indol-9-yl]acetate
  • Step 13 (+/-)-Ethyl[10-(4-chlorophenyl)-1-(methylsulfinyl)-6,7,5,9-tetrahydropyrido[1,2- a ]indol-9-yl] acetate
  • Step 14 (+/-)-[10-(4-Chlorophenyl)-1-(methylsulfinyl)-6,7,8,9-tetrahydropyrido[1,2- a ]indol-9-yl]acetic acid
  • Step 2 4-Bromo-1-(triisopropylsilyl)-1 H -indole
  • Step 3 4-(Methylsulfanyl)-1-(triisopropylsilyl)-1 H -indole
  • Step 4 3-Bromo-1-(triisopropylsilyl)-1 H -indol-4-yl methyl sulfide
  • Step 5 3-(4-chlorobenzyl)-1-(triisopropylsilyl)-1 H -indol-4-yl methyl sulfide
  • Step 6 3-(4-Chlorobenzyl)-1 H -indol-4-yl methyl sulfide
  • Step 7 2-Bromo-3-(4-chlorobenzyl)-1 H -indol-4-yl methyl sulfide
  • Step 8 Ethyl 4-[2-bromo-3-(4-chlorobenzyl)-4-(methylsulfanyl)-1 H -indol-1-yl]butanoate
  • Step 9 4-[2-Bromo-3-(4-chlorobenzyl)-4-(methylsulfanyl)-1 H -indol-1-yl]butanal
  • Step 10 Ethyl(2 E , Z )-6-[2-bromo-3-(4-chlorobenzyl)-4-(methylsulfanyl)-1 H- indol-1-yl]-2-hexenoate
  • Step 11 Ethyl(2 E , Z )-(10-(4-chlorobenzyl)-1-(methylsulfanyl)-7,8-dihydropyrido[1,2- a ]indol-9(6 H )-ylidene)ethanoate
  • Step 12 (+/-)-Ethyl[10-(4-chlorobenzyl)-1-(methylsulfanyl)-6,7,8,9-tetrahydropyrido[1,2- a ]indol-9-yl] acetate
  • Step 13 (+/-)-Ethyl[10-(4-chlorobenzyl)-1-(methylsulfinyl)-6,7,8,9-tetrahydropyrido[1,2- a ]indol-9-yl]acetate
  • Step 14 (+/-)-[10-(4-Chlorobenzyl)-1-(methylsulfinyl)-6,7,8,9-tetrahydropyrido[1,2- a ]indol-9-yl]acetic acid
  • Step 3 Methyl (2 E ,Z)-2-azido-3-(2-bromo-4-fluorophenyl)-2-propenoate
  • Step 4 Methyl 4-bromo-6-fluoro-1 H -indole-2-carboxylate
  • Step 5 ( +/-)-Methyl 8-bromo-6-fluoro-1-oxo-2,3-dihydro-1 H -pyrrolo[1,2- a ]indole-2-carboxylate
  • Step 6 8-Bromo-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-one
  • Step 7 (+/-)-Methyl(8-bromo-6-fluoro-1-hydroxy-2,3-dihydro-1 H- pyrrolo [ 1,2- a ]indol-1-yl)acetate
  • Step 8 (+/-)-Methyl(8-bromo-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetate
  • Step 9 (+/-)-Methyl [8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 10 (+/-)-[8-Bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 (+/-)-(8-bromo-6-fluoro-2,3-dihydro-1 H -pyrrolo-[1,2- a ]indol-1-yl)acetic acid
  • (+/-)-methyl (8-bromo-6-fluoro-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl)acetate (11g) in a THF/MeOH (3:1) mixture at r.t. was added 1N LiOH (50 mL, aqueous solution). The reaction mixture was stirred at r.t. for 12 hours and AcOH (5 mL) and brine (100 mL) were added. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na 2 SO 4 and concentrated to provide the title compound as a white solid.
  • Step 2 (4 S )-4-benzyl-3-[(8-bromo-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetyl]-1,3-oxazolidin-2-one
  • Step 3 (4 S )-4-benzyl-3-[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetyl)-1,3-oxazolidin-2-one
  • Step 4 (+)-[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 Methyl 4-bromo-3-[(4-chlorophenyl)sulfanyl]-6-fluoro-1 H- indole-2-carboxylate
  • Step 2 Methyl 4-bromo-3- [ (4-chlorophenyl)sulfanyl]-1-(4-ethoxy-4-oxobutyl)-6-fluoro-1 H -indole-2-carboxylate
  • Step 3 (+/-)-Ethyl 1-bromo-10-[(4-chlorophenyl)sulfanyl]-3-fluoro-9-oxo-6,7,8,9-tetrahydropyrido[1,2- a ]indole-8-carboxylate
  • Step 4 1-Bromo-10-[(4-chlorophenyl)sulfanyl]-3-fluoro-7,8-dihydropyrido[1,2- a ]indol-9(6 H )-one
  • Step 5 (+/-)-Methyl [1-bromo-10-[(4-chlorophenyl)sulfanyl]-3-fluoro-9-hydroxy-6,7,8,9-tetrahydropyrido[1,2- a ]indol-9-yl]acetate
  • Step 6 (+/-)-Methyl [1-bromo-10-[(4-chlorophenyl)sulfanyl]-3-fluoro-6,7,8,9-tetrahydropyrido[1,2- a ]indol-9-yl]acetate
  • Step 7 (+/-)-[1-Bromo-10-[(4-chlorophenyl)sulfanyl]-3-fluoro-6,7,8,9-tetrahydropyrido[1,2- a ]indol-9-yl]acetic acid
  • Step 2 1-Methoxy-3-(methylsulfanyl)-6,7,8,9-tetrahydropyrido[1,2- a ]indol-9-one
  • Step 3 1-Methoxy-3-(methylsulfonyl)-6,7,8,9-tetrahydropyrido [ 1,2- a ]indol-9-one
  • Step 4 E/Z- Ethyl 2-[1-methoxy-3-(methylsulfonyl)-6,7,8,9-tetrahydropyrido[1,2- a ]indol-9-yliden]acetate
  • Step 5 Ethyl 2-[1-methoxy-3-(methylsulfonyl)-6,7,8,9-tetrahydropyrido[1,2- a ]indol-9-yl] acetate
  • Step 6 (+/-)-[10-[(4-Chlorophenyl)sulfanyl]-1-methoxy-3-(methylsulfonyl)-6,7,8,9-tetrahydropyrido[1,2- a ]indol-9-yl]acetic acid
  • Step 1 (+/-)-Methyl[8-acetyl-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • (+/-)-methyl[8-bromo-9-[(4-chlorophenyl)sulfunyl]-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate (Example 7, 235 mg, 0.5 mmol) in 2 mL of DMF and 1-ethoxyvinyltri-n-butyltin (451 mg, 1.3 mmol) were added and the mixture was degassed. The reaction mixture was stirred at 90°C for 12 hours and 1N HCl (4 mL) was added. The mixture was stirred at 90°C for 2 hours and extracted with EtOAc.
  • Step 2 (+/-)-[8-Acetyl-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 (+/-)-[9-[(4-Chlorophenyl)sulfanyl]-6-fluoro-8-(trifluoroacetyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • (+/-)-[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro- 1H -pyrrolo[1,2- a ]indol-1-yl]acetic acid (Example 7, 250 mg, 0.6 mmol) in THF (8 mL) at -78°C was added 3M MeMgBr (0.7 mmol) followed by the addition of sec-BuLi (0.8 mmol, 1.3M solution). The reaction mixture was stirred at -78°C for 5 minutes and methyl trifluoroacetate (352 mg, 2.8 mmol) was added.
  • the reaction mixture was warmed to r.t., stirred for 4 hours and saturated aqueous NH 4 Cl was added. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography eluted with EtOAc/Hexanes/AcOH (20:30:1) to provide 150 mg of the title compound as a white solid.
  • (+/-)-[9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(trifluoroacetyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol- 1-yl]acetic acid (Example 11, 78 mg) in MeOH (5 mL) at r.t. was added 50 mg of NaBH 4 . The reaction mixture was stirred at r.t. for 3 hours and 1N HCl was slowly added The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na 2 SO 4 and concentrated.
  • (+/-)-[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid (Example 7, 100 mg, 0.22 mmol) in THF (4 mL) at -78°C was added 3M MeMgBr (0.26 mmol) followed by the addition of 1.3M sec-BuLi (0.31 mmol). The reaction mixture was stirred at -78°C for 20 minutes and an excess of isobutyraldehyde was added.
  • the reaction mixture was slowly warmed to -20°C over a 30 minute period and quenched with saturated aqueous NH 4 Cl. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 and concentrated. The residue was purified by preparative HPLC using a Zorbax column eluted with 10% iPrOH in Hexanes containing 0.2% of AcOH to provide 40 mg of the title compound as a white solid.
  • (+/-)-[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid (Example 7, 100 mg, 0.22 mmol) in THF (4 mL) at -78°C was added 3M MeMgBr (0.26 mmol) followed by the addition of 1.3M sec-BuLi (0.31 mmol). The reaction mixture was stirred at -78°C for 5 minutes and an excess of acetaldehyde was added.
  • Step 1 (+/-)-Methyl [9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(1-hydroxyethyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • (+/-)- [9-[(4-Chlorophenyl)sulfanyl]-6-fluoro-8-(1-hydroxyethyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid (Example 14, 100 mg) was esterified in Et 2 O by addition of an excess of CH 2 N 2 . After removal of the solvents, the title ester was obtained quantitatively as a pale yellow solid and used as such.
  • Step 2 (+/-)-Methyl[9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(1-methoxyethyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl] acetate
  • Step 3 (+/-)-[9-[(4-Chlorophenyl)sulfanyl]-6-fluoro-8-(1-methoxyethyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 [9-[(4-Chlorophenyl)sulfanyl]-6-fluoro-8-(1-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetic acid
  • Step 2 [9-[(4-Chlorophenyl)sulfanyl]-6-fluoro-8-(1-methoxyethyl)-2,3-dihydro-1 h -pyrrolo[1,2-a]indol-1-yl]acetic acid
  • Step 1 (+/-)-Methyl(8-acetyl-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetate
  • the reaction mixture was stirred at 90°C for 12 hours and 1N HCl (4 mL) was added.
  • the mixture was stirred at 90°C for 12 hours and extracted with EtOAc.
  • the combined organic layers were washed with 1N HCl, brine and water, dried over Na 2 SO 4 and concentrated.
  • the residue was purified by silica gel chromatography eluted with 20% EtOAc in hexanes to provide the title compound (70% pure) as a pale yellow oil used as such.
  • Step 2 (+/-)-Methyl[8-acetyl-6-fluoro-9-(phenylsulfanyl)-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 3 (+/-)-[8-Acetyl-6-fluoro-9-(phenylsulfanyl)-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 (+/-)-Methyl[8-acetyl-9-[(3,4-dichlorophenynl)sulfanyl]-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 2 (+/-)-[8-Acetyl-9-[(3,4-dichlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 (+/-)-Methyl[9-[(4-chloropbenyl)sulfanyl]-6-fluoro-8-(2,2,2-trifluoro-1-methoxyethyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • (+/-)-[9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid (Example 12, 27 mg, 0.07 mmol) in DMF (4 mL) at 0°C was added NaH (24 mg, 0.6 mmol, 60% in oil). The reaction mixture was stirred at 0°C for 15 minutes and methyl iodide (52 mg, 0.36 mmol) was added. The reaction mixture was stirred for 15 minutes and quenched with saturated aqueous NH 4 Cl and extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 , concentrated and used as such.
  • Step 2 (+/-)-[9-[(4-Chlorophenyl)sulfanyl]-6-fluoro-8-(2,2,2-trifluoro-1-methoxyethyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • (+)-[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro- 1H -pyrrolo[1,2- a ]indol-1-yl]acetic acid (Example 7A, 700 mg, 1.5 mmol) in THF (15 mL) at -78°C was added 3M MeMgBr in THF(1.9 mmol) followed by the addition of 1.6M nBuLi in hexane(3.1 mmol). The reaction mixture was stirred at -78°C for 2 minutes and an excess of propionaldehyde was added.
  • reaction mixture was stirred at -78°C for 15 minutes, warmed to r.t and quenched with saturated aqueous NH 4 Cl
  • the phases were separated and the aqueous layer was extracted with EtOAc.
  • the combined organic layers were dried over Na 2 SO 4 and concentrated.
  • the residue was purified by silica gel chromatography eluted with EtOAc/hexanes/AcOH (20:30:1) to provide the title compound as a white solid.
  • Step 1 Methyl [9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(1-methoxypropyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 2 [9-[(4-Chlorophenyl)sulfanyl]1-6-fluoro-8-(1-methoxypropyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 The ester of Step 1 (540 mg) was hydrolyzed using the procedure described in Example 10, Step 2 to provide the title compound (mixture of 2 diastereomers) as a yellow syrup.
  • the two diastereomers were separated by preparative HPLC on a chiralpak A/D preparative column eluted with a mixture of 5% iPrOH in hexanes + 0.2% AcOH, to give isomer A (less polar isomer) and isomer B (more polar isomer) as a white foam.
  • Methanethiol was bubbled into a solution of [9-[(4-chlorophenyl)-sulfanyl]-6-fluoro-8-(1-hydroxyethyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid (Example 15A, Step 1, 48 mg, 0.1 mmol) in 5 mL of dichloromethane at 0°C and zinc iodide (5 mg, 0.015 mmol) was added. The reaction mixture was stirred at 0°C for 15 minutes and quenched with saturated aqueous NH 4 Cl and extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 and concentrated.
  • Step 4 8-Bromo-6-methoxy-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-one
  • Step 5 Methyl(8-bromo-6-methoxy-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetate
  • Step 6 Methyl ⁇ 8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-methoxy-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl ⁇ acetate
  • Step 7 Methyl [9-[(4-chlorophenyl)sulfanyl]-6-methoxy-8-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 8 [9-[(4-chlorophenyl)sulfanyl]-6-methoxy-8-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 Methyl[6-methoxy-8-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]-indol-1-yl]acetate
  • Example 22 Step 7 the title compound was prepared from the bromide of Example 22 Step 5.
  • Step 2 Methyl[6-hydroxy-8-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]-indol-1-yl]acetate
  • Step 3 Methyl[6-(benzyloxy)-8-(methylsulfonyl)-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 4 Methyl[6-(benzyloxy)-9-[(4-chlorophenyl)sulfanyl]-8-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ⁇ indol-1-yl]acetate
  • Step 5 [6-(benzyloxy)-9-[(4-chlorophenyl)sulfanyl]-8-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 2 (+/-)-[9-[(4-chlorophenyl)thiol-8-(methylsulfonyl)-6-methylthio)-2,3-dihydro-1H-pyrrolo[1-2-a]indol-1-yl]acetic acid
  • Step 1 Methyl[8-bromo-6-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]inidol-1-yl]acetate
  • Step 2 Methyl [8-isopropenyl-6-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 3 Methyl[8-isopropyl-6-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetate
  • Step 2 To the product of Step 2 (130 mg, 0.39 mmol) in EtOH (3 mL) was added Pd/C 10% (40 mg). The mixture was hydrogenated with a Parr hydrogenator at 50 psi for 45 minutes, filtered on a pad of celite, and the filtrate evaporated to dryness and used as such in the next step.
  • Step 4 Methyl[9-[(4-chlorophenyl)thio]-8-isopropyl-6-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 5 [9-[(4-chlorophenyl)thiol-8-isopropyl-6-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 Methyl [6-isopropoxy-8-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 2 Methyl[9-[(4-chlorophenyl)thiol]-6-isopropoxy-8-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 3 (+/-)-[9-[(4-chlorophenyl)thio]-6-isopropoxy-8-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 Methyl (8-isopropenyl-6-methoxy-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetate
  • Step 2 Methyl(8-isopropyl-6-methoxy-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 2 To the compound of Step 1 (200 mg, 0.67 mmol) in EtOH (20 mL) was added Pd/C 10% (100 mg). The mixture was hydrogenated with a Parr hydrogenator at 50 psi for 45 minutes the filtered on a pad of celite. The filtrate was evaporated to dryness and used as such in the next step (170 mg).
  • Step 3 Methyl (6-hydroxy-8-isopropyl-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetate
  • Step 4 Methyl [6-(benzyloxy)-8-isopropyl-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 5 Methyl ⁇ 6-(benzyloxy)-9[(4-chlorophenyl)thio]-8-isopropyl-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl ⁇ acetate
  • Step 6 (+/-)- ⁇ 6-(benzyloxy)-9-[4-chlorophenyl)thio]-8-isopropyl-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl ] acetic acid
  • Example 27 The procedures of Example 27, Steps 1, 2, 5 and 6 were followed using the product of Example 22, Step 5 to provide the title compound.
  • 1 H NMR (acetone d6) ⁇ 1.18(m 3H), 1.22(m, 3H), 2.32(m, 1H), 2.60(m, 1H), 2.85(m, 1H), 3.15(m, 1H), 3.72 (m, 3H), 3.98(s, 1H), 4.33(m, 1H),4.45(m,1H),4.65(m,1H) 7.00(m, 1H), 7.08(m, 3H), 7.25(m, 2H),
  • Step 1 Methyl (8-(methylsulfonyl)-6- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ -2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetate
  • Step 2 Methyl (9-[(4-chlorophenyl)thio]-8-methylsulfonyl)-6- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ -2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl ) acetate
  • Step 3 Methyl [6-(4-chlorophenyl)-9-[(4-chlorophenyl)thio]-8-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 4 (+/-)-[6-(4-chlorophenyl)-9-[(4-chlorophenyl)thio]-8-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 2 (+/-)- ⁇ 8-bromo-9-[(4-chlorophenyl)thio]-6-iodo-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl ⁇ acetic acid
  • Step 1 (+/-)-methyl ⁇ 8-bromo-9-[(4-chlorophenyl)thio]-6-cyano-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl ⁇ acetate
  • (+/-)-methyl ⁇ 8-bromo-9-[(4-chlorophenyl)thio]-6-iodo-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl ⁇ acetate (see Example 30, 2.5 g, 4.3 mmol) in DMF (40 mL) were added zinc cyanide (1.27g, 10.8 mmol), tris-(dibenzylideneacetone)dipalladium(0) (197 mg, 0.21 mmol), H 2 O (43mmol) and 1,1'-bis(diphenylphosphino)ferrocene (120 mg, 0.21 mmol), and N 2 was bubbled for 2 minutes into the mixture.
  • Step 2 (+/-)- ⁇ 8-bromo-9-[(4-chlorophenyl)thio]-6-cyano-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl ⁇ acetic acid
  • Step 1 (+/-)-methyl[8-bromo-9-[(4-chlorophenyl)thio]-6-(2 H -tetrazol-5-yl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 2 (+/-)-[8-bromo-9-[(4-chlorophenyl)thio]-6-(2-methyl-2 H -tetrazol-5-yl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 (+/-)-[8-acetyl-9-[(4-chlorophenyl)thio]-6-(2-methyl-2 H -tetrazol-5-yl)-2,3-dihydro-1 H -pyrrolo [ 1,2- a ]indol-1-yl]acetic acid
  • Step 1 (+/-)-methyl[6-fluoro-8-(methylthio)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • (+/-)-(8-bromo-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetic acid (Example 7A, Step 1, 400 mg, 1.3 mmol) in THF (10 mL) at -78°C was added 3M MeMgBr (1.5 mmol) followed by the addition ofn-BuLi (2.6 mmol, 1.6M solution). The reaction mixture was stirred at -78°C for 5 minutes and an excess of methyl disulfide (300 mg) was added. The reaction mixture was warmed to r.t. and stirred for 15 minutes and 1N HCl was added.
  • Step 2 (+/-)-methyl[6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 3 (+/-)-[9-[(4-chlorophenyl)thio]-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 [(1 R )-9-[(4-chlorophenyl)thio]-6-fluoro-8-(methylsulfonyl)-2,3-dilhydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 (+/-)-methyl [8-(ethylthio)-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 2 (+/-)-[9-[(4-chlorophenyl)thio]-8-ethylsulfonyl)-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Sten 1 (4 S )-4-benzyl-3- ⁇ [9-[(4-chlorophenyl)thio]-6-fluoro-8-(1-methyl-1 H- pyrrol-2-yl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetyl ⁇ -1,3-oxazolidin-2-one
  • Step 2 [(1 R )-9-[(4-chlorophenyl)thio]-6-fluoro-8-(1-methyl-1 H -pyrrol-2-yl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 (+/-)-methyl [9-[(4-chlorophenyl)thio]-6-fluoro-8-(1-hydroxyethyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 2 (+/-)- ⁇ 9-[(4-chlorophenyl)thio]-8-ethyl-6-fluoro-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl ⁇ acetic acid
  • Step 1 (+/-)-methyl (6-fluoro-8-isopropenyl-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetate
  • (+/-)-methyl (8-bromo-6-fluoro-2,3 -dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetate (Example 7, Step 8, 1g, 3.1 mmol in 5 mL of THF) was added.
  • the reaction mixture was stirred at 55°C for 2 hours, cooled to r.t., poured into 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography eluted with 20% EtOAc/hexane to give 600 mg of the title compound as a pale yellow oil.
  • Step 2 (+/-)-methyl(6-fluoro-8-isopropyl-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetate
  • Step 3 (+/-)- ⁇ 9-[(4-chlorophenyl)thio]-6-fluoro-5-isopropyl-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl ⁇ acetic acid
  • Step 1 methyl [(1 R )-6-fluoro-8-isopropyl-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 2 ⁇ (1 R )-9-[(4-chlorophenyl)thio]-6-fluoro-8-isopropyl-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl ⁇ acetic acid
  • Step 1 (+/-)-methyl [8-(1-ethyl-1-hydroxypropyl)-6-fluoro-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl]acetate
  • (+/-)-(8-bromo-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetic acid (Example 7A, Step 1)
  • 500 mg, 1.6 mmol) in THF (10 mL) at -78°C was added 3M MeMgBr (1.9 mmol) followed by the addition of n-BuLi (4.8 mmol, 1.6M solution).
  • the reaction mixture was stirred at -78°C for 5 minutes and an excess of 3-pentanone (700 mg) was added.
  • the reaction mixture was warmed to r.t. and stirred for 15 minutes.
  • Step 2 (+/-)-methyl[8-(1-ethylpropyl)-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 3 (+/-)-[9-[(4-chlorophenyl)thio]-8-(1-ethylpropyl)-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 (+/-)-methyl (8-cyclopent-1-en-1-yl-6-fluoro-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl)acetate
  • (+/-)-methyl (8-bromo-6-fluoro-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl)acetate (Example 7, Step 8, 300 mg, 0.92 mmol) and tributyl(cyclopent-1-en-1-yl)stannane, the title compound (150 mg) was synthesized as described in Example 42 as a pale yellow oil.
  • Step 2 (+/-)-methyl (8-cyclopentyl-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetate
  • Step 3 (+/-)- ⁇ 9-[(4-chlorophenyl)thio]-8-cyclopentyl-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl ⁇ acetic acid
  • Step 1 (+/-)-methyl ⁇ 6-fluoro-8-[2,2 2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl ⁇ acetate
  • Step 2 (+/-)- ⁇ 9-[(4-chlorophenyl)thio]-6-fluoro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl ⁇ -acetic acid
  • Step 1 (+/-)-methyl ⁇ 8-bromo-9-[(4-chlorophenyl)thio]-6-cyclopropyl-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl ⁇ acetate
  • Step 2 (+/-)-[9-[(4-chlorophenyl)thio]-6-cyclopropyl-8-(1-methyl-1 H -pyrrol-2-yl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 (+/-)-methyl (6-fluoro-8-vinyl-2.3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetate
  • (+/-)-methyl (8-bromo-6-fluoro-2,3-dihydro-1 H pyrrolo[1,2- a ]indol-1-yl)acetate (Example 7, Step 8, 330 mg, 1 mmol) in DMF (4 mL) were added Tris(dibenzylideneacetone)dipalladium(0) (92 mg, 0.1 mmol), triphenyl arsine (122 mg, 0.4 mmol) and tributyl(vinyl)stannane (475 mg, 1.5 mmol). The mixture was degassed and stirred at 60°C for 12 hours. The reaction was poured in 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography eluted with 20% EtOAc/hexane to give 200 mg of the title compound as an yellow oil.
  • Step 2 (+/-)-methyl (8-cyclopropyl-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetate
  • Step 3 (+/-)- ⁇ 9-[(4-chlorophenyl)thio]-8-cyclopropyl-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl ⁇ acetic acid
  • Step 1 (+/-)-methyl[8-bromo-9-(4-chlorobenzyl)-6-fluoro-2,3-dihydro-1 H- pyrrolo[1,2- a ,]indol-1-yl] acetate
  • Step 2 (+/-)[8-bromo-9-(4-chlorobenzyl)-6-fluoro-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 (+/-)-methyl[8-bromo-9-(4-chlorobenzoyl)-6-fluoro-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 2 (+/-)-[9-(4-chlorobenzoyl)-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 [(1 R )-8-bromo-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • (+/-)-(8-Bromo-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetic acid (Example 7A, Step 1) was resolved by preparative HPLC on a chiralpak A/D preparative column eluted with 5% iPrOH/hexane containing 0.2% AcOH. The less polar isomer (shorter retention time) was identified as [(1 R )-8-bromo-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid.
  • Step 2 methyl[(1 R )-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 3 [(1 R )-9-(4-chlorobenzyl)-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 (+/-)-methyl ⁇ 6-fluoro-8-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl ⁇ acetate
  • Step 2 (+/-)- ⁇ 9-[(4-chlorophenyl)thio]-6-fluoro-8-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl ⁇ -acetic acid
  • (+/-)-[8-bromo-9-(4-chlorobenzoyl)-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid (Example 69)
  • the title compound was synthesized following the procedures described in Step 1 of Example 19, Step 1 of Example 20 and Step 10 of Example 7.
  • Step 1 (+/-)-methyl [8-bromo-6-fluoro-9-(2,4,6-trichlorobenzyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 2 (+/-)-[6-fluoro-8-(methylsulfonyl)-9-(2,4,6-trichlorobenzyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 (+/-)-methyl ⁇ 8-bromo-6-fluoro-9-[(2,4,5-trichlorophenyl)thio]-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl ⁇ acetate
  • Step 2 (+/-)- ⁇ 6-fluoro-8-(methylsulfonyl)-9-[(2,4,5-trichlorophenyl)thio]-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl ⁇ acetic acid
  • Step 1 (+/-)-methyl [8-bromo-6-fluoro-9-(2-naphthoyl)-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 2 (+/-)-[6-fluoro-8-(methylsulfonyl)-9-(2-naphthoyl)-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 (4-bromo-6-fluoro-1 H -indol-2-yl)methanol
  • Step 2 4-bromo-6-fluoro-1 H -indole-2-carbaldehyde
  • Step 3 ethyl-3-(4-bromo-6-fluoro-1 H -indol-2-yl)prop-2-enoate
  • Step 4 (+/-)-ethyl 8-bromo-1-(2-ethoxy-2-oxoethyl)-6-fluoro-3-oxo-2,3-dihydro-1 H -pyrrolo[1,2- a ]indole-2-carboxylate
  • Step 5 (+/-)-ethyl (8-bromo-6-fluoro-3-oxo-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetate
  • Step 6 (+/-)-ethyl ⁇ 8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-3-oxo-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl ⁇ acetate
  • Step 7 (+/-)-ethyl[9-[(4-chlorophenyl)thio]-6-fluoro-8-(methylsulfonyl)-3-oxo-2 3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 8 (+/-)-[9-[(4-chlorophenyl)thio]-6-fluoro-8-(methylsulfonyl)-3-oxo-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • (+/-)-methyl (8-bromo-6-fluoro-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl)acetate (Example 7, Step 8) and 4-chloro-2-iodobenzoyl chloride, the title compound was synthesized following the procedures described in Step 1 of Example 61 and Step 10 of Example 7. MS (-APCI) m/z 576.0 (M-H) - .
  • Step 1 (+/-)-methyl [8-bromo-9-(4-chloro-2-cyanobenzoyl)-6-fluoro-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 2 (+/-)- ⁇ 9-[2-(aminocarbonyl)-4-chlorobenzoyl]-8-bromo-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl ⁇ acetic acid
  • Step 2 methyl ((1 R )-8-bromo-6-fluoro-9- ⁇ [4-(trifluoromethyl)phenyl]thio ⁇ -2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetate
  • Step 3 ((1 R )-6-fluoro-8-(methylsulfonyl)-9- ⁇ [4-(trifluoromethyl)phenyl]thio ⁇ -2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetic acid
  • Step 2 methyl ⁇ (1 R )-8-bromo-9-[(4-bromophenyl)thio]-6-fluoro-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl ⁇ acetate
  • Example 62A Starting from 1-bromo-4-[(4-bromophenyl)dithio]benzene and methyl [(1 R )-8-bromo-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate (Example 62A), the title compound was synthesized following the procedures described in Step 9 of Example 7.
  • Step 3 ((1 R )-6-fluoro-8-(methylsulfonyl)-9- ⁇ [4-(methylsulfonyl)phenyl]thio ⁇ -2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetic acid
  • Step 2 (+/-)-[9-(1,3-benzothiazol-2-ylthio)-8-bromo-6-fluoro-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 1 (+/-)- tert -butyl [8-bromo-9-(4-chlorobenzoyl)-6-fluoro-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl]acetate
  • (+/-)-[8-bromo-9-(4-chlorobenzoyl)-6-fluoro-2,3-dihydro-1 H- pyrrolo[1,2- a ]indol-1-yl]acetic acid (Example 69, 500 mg) in toluene (10 mL) at 100°C was slowly added 1,1-di tert -butoxy- N,N -dimethylmethanamine (0.7 mL). The mixture was stirred at 110°C for 1h, cooled to r.t., washed with aqueous saturated NaHCO 3 and brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography eluted with 30%EtOAc/hexaxe to give 410 mg of the title compound.
  • Step 2 (+/-)- tert -butyl ⁇ 8-bromo-9-[1-(4-chlorophenyl)vinyl]-6-fluoro-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl ⁇ acetate
  • Step 3 (+/-)- tert -butyl [9-[1-(4-chlorophenyl)vinyl]-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 4 (+/-)- tert -butyl [9-[1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetate
  • Step 4 (+/-)-[9-[1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 2 (+/-)-[6-fluoro-8-isopropyl-9-(1-naphthylthio)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Example 44 Starting from 1-(1-naphthyldithio)naphthalene and (+/-)-methyl (6-fluoro-8-isopropyl-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl)acetate (Example 44, Step 1), the title compound was synthesized following the procedures described in Step 9 of Example 7 and Step 10 of Example 7. MS (-APCI) m/z 432.0 (M-H) - .
  • Step 2 (+/-)-[6-fluoro-8-isopropyl-9-(2-naphthylthio)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid
  • Step 2 (+/-)-[8-bromo-6-fluoro-9-(pyrimidin-2-ylthio)-2,3-dihydro-1 H -pyrrolo[1,2- a ]indol-1-yl]acetic acid

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Families Citing this family (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1558614B1 (en) 2002-10-30 2010-09-01 Merck Frosst Canada Ltd. Pyridopyrrolizine and pyridoindolizine derivatives
EP1585511B1 (en) 2002-12-20 2013-01-23 Amgen Inc. Asthma and allergic inflammation modulators
AR041089A1 (es) 2003-05-15 2005-05-04 Merck & Co Inc Procedimiento y composiciones farmaceutiicas para tratar aterosclerosis, dislipidemias y afecciones relacionadas
PE20050483A1 (es) 2003-10-31 2005-08-25 Arena Pharm Inc Derivados de tetrazol de formula (i), sus composiciones farmaceuticas y procesos para producir composiciones farmaceuticas
CN1930162B (zh) 2004-03-11 2010-06-16 埃科特莱茵药品有限公司 四氢吡啶并吲哚衍生物
ITMI20040874A1 (it) * 2004-04-30 2004-07-30 Ist Naz Stud Cura Dei Tumori Derivati indolici ed azaindolici con azione antitumorale
WO2006052798A2 (en) * 2004-11-08 2006-05-18 Merck & Co., Inc. Method of treating pathological blushing
PE20060949A1 (es) 2004-12-23 2006-10-11 Arena Pharm Inc Derivados fusionados de pirazol como agonistas del receptor de niacina
BRPI0519280A2 (pt) 2004-12-27 2009-01-06 Actelion Pharmaceuticals Ltd composto, composiÇço farmacÊutica e uso de um composto
KR20070113295A (ko) * 2005-03-17 2007-11-28 노파르티스 아게 티로신/트레오닌 키나제 억제제, 특히 ｂ-ｒａｆ 키나제억제제로서의ｎ-[3-(1-아미노-5,6,7,8-테트라히드로-2,4,4ｂ-트리아자플루오렌-9-일)-페닐]벤즈아미드
EP1916245B1 (en) 2005-07-22 2011-10-26 Shionogi & Co., Ltd. Indole derivative having pgd2 receptor antagonist activity
WO2007010965A1 (ja) 2005-07-22 2007-01-25 Shionogi & Co., Ltd. Ｐｇｄ２受容体アンタゴニスト活性を有するアザインドール酸誘導体
JP4972644B2 (ja) * 2005-08-12 2012-07-11 メルク カナダ インコーポレイテッド Ｃｒｔｈ２受容体拮抗薬としてのインドール誘導体
JP5147401B2 (ja) 2005-09-06 2013-02-20 塩野義製薬株式会社 Ｐｇｄ２受容体アンタゴニスト活性を有するインドールカルボン酸誘導体
AU2007282949B8 (en) 2006-08-07 2012-10-04 Actelion Pharmaceuticals Ltd. (3-Amino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid derivatives
CN101896178B (zh) * 2007-10-10 2013-11-20 北京赛林泰医药技术有限公司 作为crth2受体拮抗剂的杂环化合物
WO2009085177A1 (en) 2007-12-19 2009-07-09 Amgen Inc. Phenyl acetic acid derivatives as inflammation modulators
US20110098352A1 (en) * 2008-02-01 2011-04-28 Amira Pharmaceuticals, Inc. N,n-disubstituted aminoalkylbiphenyl antagonists of prostaglandin d2 receptors
EA018901B1 (ru) 2008-02-01 2013-11-29 ПАНМИРА ФАРМАСЬЮТИКАЛС, ЭлЭлСи N,n-дизамещенные аминоалкилбифенилы в качестве антагонистов рецепторов простагландина d
EP2257536A4 (en) * 2008-02-14 2011-03-23 Amira Pharmaceuticals Inc CYCLIC DIARYL ETHERS AS ANTAGONISTS OF PROSTAGLANDIN D2 RECEPTORS
EP2245022A4 (en) 2008-02-25 2012-02-22 Panmira Pharmaceuticals Llc ANTAGONISTS OF PROSTAGLANDIN D2 RECEPTORS
EP2268611A2 (en) * 2008-04-02 2011-01-05 Amira Pharmaceuticals, Inc. Aminoalkylphenyl antagonists of prostaglandin d2 receptors
US20110112134A1 (en) * 2008-05-16 2011-05-12 Amira Pharmaceuticals, Inc. Tricyclic Antagonists of Prostaglandin D2 Receptors
US8501959B2 (en) * 2008-06-24 2013-08-06 Panmira Pharmaceuticals, Llc Cycloalkane[B]indole antagonists of prostaglandin D2 receptors
US8071807B2 (en) * 2008-07-03 2011-12-06 Panmira Pharmaceuticals, Llc Antagonists of prostaglandin D2 receptors
US8507473B2 (en) 2008-09-11 2013-08-13 Arena Pharmaceuticals, Inc. 3H-imidazo[4,5-b]pyridin-5-ol derivatives useful in the treatment of GPR81 receptor disorders
GB2463788B (en) * 2008-09-29 2010-12-15 Amira Pharmaceuticals Inc Heteroaryl antagonists of prostaglandin D2 receptors
WO2010042652A2 (en) 2008-10-08 2010-04-15 Amira Pharmaceuticals, Inc. Heteroalkyl biphenyl antagonists of prostaglandin d2 receptors
GB2465062B (en) * 2008-11-06 2011-04-13 Amira Pharmaceuticals Inc Cycloalkane(B)azaindole antagonists of prostaglandin D2 receptors
WO2010057118A2 (en) * 2008-11-17 2010-05-20 Amira Pharmaceuticals, Inc. Heterocyclic antagonists of prostaglandin d2 receptors
US20100173313A1 (en) * 2009-01-08 2010-07-08 Amira Pharmaceuticals, Inc. Biomarkers of inflammation
SG178109A1 (en) 2009-07-31 2012-03-29 Panmira Pharmaceuticals Llc Ophthalmic pharmaceutical compositions of dp2 receptor antagonists
SG178252A1 (en) * 2009-08-05 2012-03-29 Panmira Pharmaceuticals Llc Dp2 antagonist and uses thereof
WO2011035417A1 (en) * 2009-09-25 2011-03-31 Aegera Therapeutics Inc. Hsp-90 binding compounds, compositions thereof, and their use fn the treatment of autoimmune and inflammatory diseases
SG182398A1 (en) 2010-01-06 2012-08-30 Panmira Pharmaceuticals Llc Dp2 antagonist and uses thereof
MY183111A (en) 2010-03-22 2021-02-15 Idorsia Pharmaceuticals Ltd 3-(heteroaryl-amino)-1,2,3,4-tetrahydro-9h-carbazole derivatives and their use as prostaglandin d2 receptor modulators
WO2012004722A1 (en) 2010-07-05 2012-01-12 Actelion Pharmaceuticals Ltd 1-phenyl-substituted heterocyclyl derivatives and their use as prostaglandin d2 receptor modulators
EP2606032B1 (en) * 2010-08-20 2015-01-07 University Of Washington Through Its Center For Commercialization Composition and methods for treating glioblastomas
DK3369723T3 (da) * 2011-03-02 2021-01-11 Bayer Cropscience Ag Fremgangsmåde til fremstilling af aryl- og heteroaryleddikesyrederivater
WO2012126084A1 (en) * 2011-03-24 2012-09-27 Pharmascience Inc. Hsp-90 binding compounds, compositions thereof, and their use iν the treatment and prevention of fungal infections
CA2830204C (en) 2011-04-14 2019-04-09 Actelion Pharmaceuticals Ltd 7-(heteroaryl-amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol acetic acid derivatives and their use as prostaglandin d2 receptor modulators
MX2014007688A (es) 2011-12-21 2014-07-28 Actelion Pharmaceuticals Ltd Derivados de heterociclilo y su uso como moduladores del receptor d2 de prostaglandina.
KR20150027827A (ko) 2012-07-05 2015-03-12 액테리온 파마슈티칼 리미티드 1-페닐-치환된 헤테로시클릴 유도체 및 프로스타글란딘 d2 수용체 조절제로서의 그의 용도
US9797903B2 (en) 2012-10-24 2017-10-24 Winthrop-University Hospital Non-invasive biomarker to identify subject at risk of preterm delivery
US9815796B2 (en) 2013-12-23 2017-11-14 Merck Sharp & Dohme Corp. Pyrimidone carboxamide compounds as PDE2 inhibitors
SI3119779T1 (sl) 2014-03-17 2018-10-30 Idorsia Pharmaceuticals Ltd Derivati azaindolocetne kisline in njihova uporaba kot modulatorji prostaglandinskega receptorja D2
CN106103437A (zh) 2014-03-18 2016-11-09 埃科特莱茵药品有限公司 氮杂吲哚乙酸衍生物及其作为前列腺素d2受体调节剂的用途
EP4420734A3 (en) 2015-02-13 2024-11-06 Institut National de la Santé et de la Recherche Médicale Ptgdr-1 and/or ptgdr-2 antagonists for preventing and/or treating systemic lupus erythematosus
WO2016145614A1 (en) 2015-03-17 2016-09-22 Merck Sharp & Dohme Corp. Triazolyl pyrimidinone compounds as pde2 inhibitors
WO2016154081A1 (en) 2015-03-26 2016-09-29 Merck Sharp & Dohme Corp. Pyrazolyl pyrimidinone compounds as pde2 inhibitors
WO2016209749A1 (en) 2015-06-25 2016-12-29 Merck Sharp & Dohme Corp. Substituted pyrazolo/imidazolo bicyclic compounds as pde2 inhibitors
UA123156C2 (uk) 2015-09-15 2021-02-24 Ідорсія Фармасьютікалз Лтд КРИСТАЛІЧНА ФОРМА (S)-2-(8-((5-ХЛОРПІРИМІДИН-2-ІЛ)(МЕТИЛ)АМІНО)-2-ФТОР-6,7,8,9-ТЕТРАГІДРО-5H-ПІРИДО[3,2-b]ІНДОЛ-5-ІЛ)ОЦТОВОЇ КИСЛОТИ, ЇЇ ЗАСТОСУВАННЯ ТА ФАРМАЦЕВТИЧНА КОМПОЗИЦІЯ, ЩО ЇЇ МІСТИТЬ
WO2018014867A1 (zh) * 2016-07-21 2018-01-25 正大天晴药业集团股份有限公司 作为crth2抑制剂的三并环类化合物
CN111094988A (zh) 2017-09-13 2020-05-01 普罗根尼蒂公司 先兆子痫生物标志物及相关系统和方法
EP4070113A4 (en) 2019-12-04 2023-12-20 Biora Therapeutics, Inc. ASSESSMENT OF PREECAMPSIA USING FREE AND DISSOCIATE PLACENTAL GROWTH FACTOR ASSAYS

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1241660A (en) * 1984-06-25 1988-09-06 Yvan Guindon Indole-2-alkanoic acids
KR20010041346A (ko) * 1998-02-25 2001-05-15 브루스 엠. 에이센, 토마스 제이 데스로저 포스포리파제 ａ2 억제제
AR041089A1 (es) * 2003-05-15 2005-05-04 Merck & Co Inc Procedimiento y composiciones farmaceutiicas para tratar aterosclerosis, dislipidemias y afecciones relacionadas

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